This present invention relates to benzodiazepine derivatives, which are important in the medical field. Specifically, the present invention is concerned with novel 1,5-benzodiazepine derivatives, which antagonize gastrin receptors and/or CCK-B (cholecystokinin-B) receptors, and also with medicines for preventing and/or treating diseases in which the receptors take part.
Cholecystokinin (CCK) is a gastrointestinal hormone produced at and released from the duodenal and jejunal mucosas, and is known to have actions such as pancreatic juice secretion stimulation, gallbladder contraction stimulation and insulin secretion stimulation. Further, CCK is also known to exist at high concentrations in the cerebral cortex, the hypothalamus and the hippocampus, and is also known to have actions such as suppressing food intake, enhancing memory, generating anxiety and the like. On the other hand, gastrin is a gastrointestinal hormone produced at and released from G cells which are distributed in the pylorus, and is known to have effects such as gastric acid secretion stimulation, pylorus contraction stimulation and gallbladder contraction stimulation.
These CCK and gastrin have the same five C-terminal amino acids, and both exhibit their effects via receptors. CCK receptors are classified into peripheral CCK-As distributed in the pancreas, the gallbladder, the intestinal tract and the like and central CCK-Bs distributed in the brain. Gastrin receptors and CCK-Bs show similar properties in receptor binding experiments and have high homology, so that they may be called xe2x80x9cCCK-Bs/gastrin receptorsxe2x80x9d. Antagonistic compounds to these receptors, for example, gastrin receptors or CCK-B receptors can be used for the treatment and/or prevention of gastric ulcer, duodenal ulcer, gastritis, reflux esophagitis, pancreatitis, Zollinger-Ellison syndrome, vacuolating G cell hyperplasia, basal mucosa hyperplasia, cholecystitis, biliary colic, gastrointestinal dysmotility, irritable bowel syndrome, certain types of tumors, eating disorder, anxiety, panic disorder, depression, schizophrenia, parkinsonism, tardive dyskinesia, Gilles de la Tourette""s syndrome, drug dependance, and drug-withdrawal symptoms. They are also expected to have effects such as induction of ataralgesia and enhancement of ataralgesia induction by opioid drugs [Folia Pharmacologica Japonica, 106, 171-180 (1995); Drugs of the Future, 18, 919-931 (1993); American Journal of Physiology, 269, G628-G646 (1995); American Journal of Physiology, 259, G184-190 (1990); European Journal of Pharmacology, 261, 257-263 (1994); Trends in Pharmacological Science, 15, 65-66 (1994)].
As a gastrin receptor antagonist, proglumide is already known as a remedy for gastric ulcer and gastritis. However, proglumide has considerably low affinity to gastrin receptors or CCK-B receptors, and has a low curative effect. Further, some benzodiazepine derivatives such as L-365,718 (devazepide, Japanese Patent Application Laid-Open(Kokai) No.63666/1986) and L-365,260 (Japanese Patent Application Laid-Open (Kokai) No. 238069/1988) have been reported to exhibit CCK-A receptor antagonism and CCK-B receptor antagonism. In addition, it is disclosed that compounds having strong CCK-B antagonism inhibit pentagastrin-stimulated acid secretion (WO 94/438, WO 95/18110). These compounds are, however, not fully satisfactory when administered in vivo. Accordingly, clinically-applicable gastrin receptor or CCK-B receptor antagonists have not been provided yet.
Compounds which can strongly bind to gastrin receptors or CCK-B receptors are useful for the prevention and/or treatment of diseases in which the respective receptors take part in the alimentary tract and the central nervous system. There is hence an outstanding desire for such compounds.
Under such circumstances, the present inventors have proceeded with an extensive investigation to solve the above-described problems. As a result, it was found that 1,5-benzodiazepine derivatives having a specific structure have strong gastrin receptor and/or CCK-B receptor antagonism and achieve strong inhibition of acid secretion and are useful as medicines for the prevention and/or treatment of diseases in which these receptors take part, and an application for patent has already been filed (PCT/JP97/04534). The present inventors have proceeded with further research. As a result, it has been found that 1,5-benzodiazepine derivatives each of which contains a branched fatty acid group achieve still better inhibition of pentagastrin-stimulated acid secretion in rats and inhibition of pentagastrin-stimulated acid secretion in beagles with Heidenhain pouch, leading to the completion of the present invention.
Therefore, the present invention provides a 1,5-benzodiazepine derivative represented by the following formula (1): 
wherein R1 represents a lower alkyl group, R2 and R3 may be the same or different and represent a hydrogen atom or a lower alkyl group, R4 represents a cyclohexyl group or phenyl group, and n stands for an integer of from 1 to 3; or a salt thereof.
The present invention also provides a medicament comprising as an effective ingredient the 1,5-benzodiazepine derivative (1) or the salt thereof.
The present invention also provides a medicinal composition comprising the 1,5-benzodiazepine derivative (1) or the salt thereof and a pharmaceutically acceptable carrier.
The present invention also provides the 1,5-benzo-diazepine derivative (1) or the salt thereof as a medicament.
The present invention further provides a treatment method of a disease in which a gastrin receptor and/or a CCK-B receptor takes part, which comprises administering the 1,5-benzo-diazepine derivative (1) or the salt thereof.
The term xe2x80x9clowerxe2x80x9d as used herein means a linear or branched carbon chain having a carbon number of from 1 to 8.
Therefore, examples of the lower alkyl groups represented by R1, R2 and R3 in the formula (1) can include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 1-methylbutyl, 2-methylbutyl, isopentyl, tert-pentyl, 1,2-dimethylpropyl, neopentyl, 1-ethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, isohexyl, 1-ethylbutyl, 2-ethylbutyl, 1,1-dimethylbutyl, 1,2-dimethyl-butyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethyl-butyl, 3,3-dimethylbutyl, 1-methyl-1-ethylpropyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, heptyl, 1-methylhexyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 1-ethylpentyl, 2-ethylpentyl, 3-ethylpentyl, 1-propylbutyl, 1-methylheptyl, 2-methylheptyl, 3-methylheptyl, 4-methylheptyl, 5-methylheptyl, 6-methyl-heptyl, 1-ethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethyl-hexyl, 1-propylpentyl, 2-propylpentyl, 3,3,4-trimethylpentyl, 3,4,4-trimethylpentyl, 1,1,2,2-tetramethylbutyl, 2,2,3,3-tetramethylbutyl, and 1,1,3,3-tetramethylbutyl. Among these, alkyl groups the carbon numbers of which range from 1 to 4 are preferred, with methyl being particularly preferred.
Compounds of the formula (1) in which R1 and R2 are methyl groups, n is 1 and R3 is a hydrogen atom, that is, of the following formula (1a) are particularly preferred: 
wherein R4 represents the same as defined above.
Illustrative of the salt of the compound (1) according to the present invention are acid addition salts with inorganic acids, such as the hydrochloride, the sulfate, the nitrate and the hydroiodate; acid addition salts with organic acids, such as the methanesulfonate and the ethanesulfonate; inorganic salts such as the sodium salt, the potassium salt, the calcium salt and the magnesium salt; and organic salts such as the ammonium salt, the pyridine salt, the triethylamine salt, the ethanolamine salt, the trans-4-aminocyclohexanol salt and the N,Nxe2x80x2-dibenzylethylenediamine salt. Among these, the sodium salt, the trans-4-aminocyclohexanol salt and the N,Nxe2x80x2-dibenzyl-ethylenediamine salt are particularly preferred.
In the present invention, the compounds (1) of the present invention and also various solvates of the compounds (1), such as their hydrates, and polymorphic substances are included. Further, racemic modifications, various diastereomers, diastereomer mixtures and optically active substances of the compounds (1) according to the present invention are all encompassed. Among these, the optically active substances are particularly preferred.
The compounds (1) of the present invention can be produced by applying various synthesis processes in view of characteristics of their fundamental structure and groups. Some representative production processes will be described hereinafter. 
wherein Boc represents a tert-butoxycarbonyl group, and R1, R2, R3, R4 and n represent the same as defined above.
Described specifically, di-tert-butyl dicarbonate is reacted with 2-amino-3-benzyloxycarbonylaminopropionic acid to obtain 2-tert-butoxycarbonylamino-3-benzyloxycarbonyl-aminopropion ic acid, followed by its debenzylation into 3-amino-2-tert-butoxycarbonylaminopropionic acid in the presence of a catalyst of palladium carbon and hydrogen. In the presence of a base such as potassium carbonate, 2-fluoronitrobenzene is reacted with 3-amino-2-tert-butoxy-carbonylaminopropionic acid to obtain 2-tert-butoxy-carbonylamino-3-(2-nitrophenyl)aminopropionic acid. This is subjected to catalytic reduction in the presence of a catalyst of palladium carbon, followed by refluxing under heat in toluene, whereby 2-oxo-3-tert-butoxycarbonylamino-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine is obtained. With this compound, 3-bromocyclohexene is reacted to obtain 2-oxo-3-tert-butoxycarbonylamino-5-(2-cyclohexen-1-yl)-1,3, 4,5-tetrahydro-2H-1,5-benzodiazepine. Hydrogenation of this compound in the presence of a catalyst of palladium carbon or platinum oxide provides the compound (A). On the other hand, dehydrogenation of 2-oxo-3-tert-butoxycarbonylamino-5-(2-cyclohexen-1-yl)-1,3,4,5-tetrahydro-2H-1,5-benzodiazep ine in the presence of nitrobenzene and a catalyst of palladium carbon or platinum oxide provides the compound (B). When bromomethyl tert-butyl ketone is reacted with the compound (A) or (B) in the presence of a base such as potassium carbonate and deprotection is then conducted by treatment with hydrochloric acid or the like, 1-tert-butylcarbonylmethyl-2-oxo-3-amino-5-cyclohexyl(or phenyl)-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine is obtained. By reacting triphosgene and a 3-aminophenyl branched fatty acid with this compound in the presence of a base such as triethylamine, the compound (1) of the present invention can be obtained. 
wherein Boc,R1, R2, R3, R4 and n represent the same meanings as defined above.
Described specifically, subsequent to deprotection of the compound (A) or compound (B) through a reaction with hydrochloric acid or the like, triphosgene and a 3-aminophenyl branched fatty acid are reacted in the presence of a base such as triethylamine, whereby a ureido derivative is obtained. By reacting bromomethyl tert-butyl ketone with the ureido derivative in the presence of a base such as potassium carbonate, the compound (1) of the present invention is obtained.
When R3is a lower alkyl group, subsequent hydrolysis with an acid or a base by a method known per se in the art makes it possible to convert the compound (1) of the present invention into another compound (1) of the present invention in which R3 is a hydrogen atom.
The compound (1) produced as described above is isolated either in a free form or as a salt, and is then purified. The isolation and purification are conducted by suitably choosing usual procedures such as extraction, concentration, distillation, crystallization, filtration, recrystallization, trituration and chromatography. Further, the compound (1) of this invention, which has been isolated and purified in the free form, can be converted into a salt with an acid or base by mixing it with the acid or base and then conducting its dissolution or the like under heat in a manner known per se in the art. Moreover, a chiral isomer of the compound (1) according to the present invention can be produced by using a suitable starting material compound. It can also be produced by general racemic resolution, for example, by converting the compound (1) of the present invention into a diastereomer salt with a general chiral acid such as dibenzoyl tartrate and then subjecting the diastereomer salt to optical resolutionorby converting it into a diastereomer compound, isolating it and then subjecting the same to Edman degradation.
The compound (1) according to the present invention or its salt can be administered either orally or parenterally. As oral dosage forms, the compound of the present invention can be formed into solid pharmaceutical preparations such as tablets, powders and capsules by suitably combining it with pharmaceutically acceptable carriers, for example, excipients such as lactose, mannitol, corn starch and crystalline cellulose; binders such as cellulose derivatives, acacia and gelatin; disintegrants such as carboxymethylcellulose calcium; and lubricants such as talc and magnesium stearate. It can also be formed into liquid pharmaceutical preparations such as liquid preparations, suspensions and emulsions.
As parenteral dosage forms, it can be formed into liquid preparations for injection, for example, by combining it with water, ethanol, glycerin and the like.
The dose of the compound (1) according to the present invention or the salt thereof, which is required to effectively treat or prevent the above-describe diseases, varies depending on the pharmaceutical preparation form, the administration route, the age and the conditions. In general, however, a daily oral dose to an adult may range from 1 to 1,000 mg, preferably from 5 to 500 mg. As an administration method, it is preferred to administer the dose once a day or in about 2 to 3 portions in a day.
As the compound (1) of the present invention or the salt thereof has strong gastrin receptor and/or CCK-B receptor antagonism and strong acid secretion inhibiting action as will be described subsequently herein, it is useful for treating, improving and/or preventing diseases in which gastrin receptors and/or CCK-B receptors take part, for example, gastric ulcer, duodenal ulcer, gastritis, reflux esophagitis, pancreatitis, Zollinger-Ellison syndrome, vacuolating G cell hyperplasia, basal mucosa hyperplasia, cholecystitis, biliary colic, gastrointestinal dysmotility, irritable bowel syndrome, certain types of tumors, eating disorder, anxiety, panic disorder, depression, schizophrenia, parkinsonism, tardive dyskinesia, Gilles de la Tourette""s syndrome, drug dependance, and drug-withdrawal symptoms, and also for inducing ataralgesia and enhancing ataralgesia induction by opioid drugs.